Three different imaging groups have demonstrated a blunting in stimulant induced dopamine release at the level of the striatum in cocaine dependent subjects. An important limitation of these studies is the fact that measurements of D2/3 receptors and amphetamine-induced dopamine release were restricted mostly to the striatum because the ligands used did not provide enough signal to noise ratio to quantify D2/3 receptors in extrastriatal regions. Given that functional imaging studies in cocaine dependence suggests a relationship between pathological activation of the prefrontal cortex (PFC) and cognitive deficits it is of extreme interest to understand the regulatory role of dopamine in this particular region. During the previous cycle of this award we validated the use of the high affinity dopamine D2/3 radiotracer [11C]FLB 457 to measure amphetamine-induced dopamine release in the PFC. In aim 1 we propose to use this recently validated imaging paradigm in a clinical study in cocaine dependence to characterize amphetamine-induced dopamine release in the PFC, and relate it to cognitive deficits and relapse. We hypothesize that amphetamine-induced dopamine release will be decreased in the mesocortical dopaminergic system in cocaine abusers relative to healthy comparison subjects and be associated with cognitive impairments and less time to relapse. Recent basic investigations postulate that an imbalance between neurotransmitters that regulate stress and anti-stress underlie negative reinforcement and relapse in addiction. Nociceptin (N/OFQ) is one such peptide neurotransmitter that exerts anti-stress effects and prevents relapse in rodent models of addiction. No previous human studies have characterized N/OFQ in addiction. In aim 2, we propose to use [11C]NOP-1A PET to measure the in vivo status of nociceptive opioid peptide (NOP) receptors in cocaine abusers, and evaluate its relationship with stress, anxiety, craving, and relapse. This aim marks a cautious first step in a new direction for this renewal application, which we intend to follow up with further experiments in cocaine dependence as novel radiotracers become available to image other components of the brain stress (e.g., corticotrophin releasing hormone, orexin, vasopressin, etc.,) and anti-stress system (neuropeptide Y).